CD4+CD25+ regulatory T (TR) cells can inhibit a variety of autoimmune and inflammatory diseases, but the precise mechanisms by which they suppress immune responses in vivo remain unresolved. Here, we have used Helicobacter hepaticus infection of T cell–reconstituted recombination-activating gene (RAG)−/− mice as a model to study the ability of CD4+CD25+ TR cells to inhibit bacterially triggered intestinal inflammation. H. hepaticus infection elicited both T cell-mediated and T cell–independent intestinal inflammation, both of which were inhibited by adoptively transferred CD4+CD25+ TR cells. T cell–independent pathology was accompanied by activation of the innate immune system that was also inhibited by CD4+CD25+ TR cells. Suppression of innate immune pathology was dependent on T cell–derived interleukin 10 and also on the production of transforming growth factor β. Thus, CD4+CD25+ TR cells do not only suppress adaptive T cell responses, but are also able to control pathology mediated by innate immune mechanisms.
Incompletely processed gastrins have been postulated to play a role in growth of the gastrointestinal tract, but few studies have examined the effects of progastrin on mucosal proliferation in vivo. Human gastrin gene expression and progastrin processing were therefore studied in transgenic mice containing a human gastrin (hGAS) minigene, and compared to processing in mice bearing an insulin gastrin (INS-GAS) transgene that overexpresses amidated gastrin. Progastrin processing was studied using region-specific antisera and radioimmunoassays, biosynthetic labeling, immunoprecipitation, and HPLC. Proliferative effects due to overexpression of processed and unprocessed gastrin in INS-GAS and hGAS mice, respectively, were determined using routine histology and BrdU incorporation. The pancreatic islets of INS-GAS mice were able to produce carboxyamidated G-17, resulting in a twofold elevation of serum amidated gastrin, marked thickening of the oxyntic mucosa, and an increased BrdU labeling index (LI) of the gastric body. In contrast, livers of adult hGAS mice expressed abundant human gastrin mRNA and human progastrin but were unable to process this peptide to the mature amidated form, resulting in markedly elevated serum progastrin levels and normal amidated gastrin levels. Nevertheless, there was a marked increase in the BrdU labeling index of the colon in hGAS mice (LI 7.46 Ϯ 1.90%), as well as in INS-GAS mice (LI 6.16 Ϯ 1.17%), compared to agematched, wild type control mice (LI 4.01 Ϯ 0.98%, P Ͻ 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo. ( J. Clin. Invest. 1996Invest. . 98:1918Invest. -1929
Helicobacter hepaticus causes hepatitis in selected strains of mice and in A/JCr mice is linked to liver cancer. To analyze whether H. hepaticus persists in specified ecological niches, to determine whether biomarkers of infection exist, and to analyze the influence of H. hepaticus on hepatocyte proliferation, a longitudinal study of H. hepaticus-infected A/JCr mice was undertaken. A/JCr mice were serially euthanatized from 3 through 18 months and surveyed by enzyme-linked immunosorbent assay; bacterial culture of liver, colon, and cecum; histology; electron microscopy; hepatocyte proliferation indices determined by using 5-bromo-2-deoxyuridine; and measurement of the liver enzyme alanine aminotransferase. In infected animals throughout the 18-month study, H. hepaticus was consistently isolated from the lower bowel but only sporadically from the liver. By electron microscopy, H. hepaticus was noted infrequently and only in bile canaliculi. Infected mice, particularly males, showed chronic inflammation; oval cell, Kupffer cell, and Ito cell hyperplasia; hepatocytomegaly; and bile duct proliferation. The inflammatory and necrotizing lesion was progressive and involved the hepatic parenchyma, portal triads, and intralobular venules. Hepatic adenomas were noted only in male mice, whereas 5-bromo-2-deoxyuridine proliferation indices were markedly increased in both sexes, but especially in males, compared with control A/J mice. Infected mice also developed sustained anti-H. hepaticus serum immunoglobulin G antibody responses and elevated alanine aminotransferase levels. H. hepaticus, which persists in the lower bowels and livers of A/JCr mice, is associated with a chronic proliferative hepatitis, and hepatomas in selected male mice indicate that this novel bacterium may cause an increased risk of hepatic cancer induction in susceptible strains of mice. This murine model should prove useful in dissecting the molecular events operable in the development of neoplasms induced by bacteria belonging to this expanding genera of pathogenic Helicobacter species.
Inflammatory bowel disease (IBD) is thought to result from either an abnormal immunological response to enteric flora or a normal immunological response to a specific pathogen. No study to date has combined both factors. The present studies were carried out with an immunologically manipulated mouse model of IBD. Mice homozygous for the severe combined immunodeficiency (scid) mutation develop IBD with adoptive transfer of CD4 ؉ T cells expressing high levels of CD45RB (CD45RB high CD4 ؉ T cells). These mice do not develop IBD in germfree conditions, implicating undefined intestinal flora in the pathogenesis of lesions. In controlled duplicate studies, the influence of a single murine pathogen, Helicobacter hepaticus, in combination with the abnormal immunological response on the development of IBD was assessed. The combination of H. hepaticus infection and CD45RB high CD4 ؉ T-cell reconstitution resulted in severe disease expression similar to that observed in human IBD. This study demonstrates that IBD develops in mice as a consequence of an abnormal immune response in the presence of a single murine pathogen, H. hepaticus. The interaction of host immunity and a single pathogen in this murine system provides a novel model of human IBD, an immunity-mediated condition triggered by bacterial infection.
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